Experimental allergic encephalomyelitis (EAE) in the SJL/J strain mouse has been intensively studied as protypical model of human multiple sclerosis. Although there is a great deal known about the role of autoreactive T cells in the induction of EAE in genetically susceptible mice, little is known about the predisposing events that are responsible for the generation and function of these abnormal T cells. The purpose of this proposal is to test the hypothesis, partly suggested by our preliminary data, that the T cell abnormalities in EAE result from intrinsic defects in prothymocytes and/or the thymic microenvironment. Specifically, we will attempt to answer the following questions: 1) Can the predisposition to acute (A) and chronic-relapsing (CR) EAE be transferred to naive recipients by SJL/J prothymocytes? 2) Does the thymic microenvironment contribute to the generation of autoreactive T cells in SJL/J mice? 3) Do other host factors also predispose SJL/J mice to EAE? 4) Does the presence, absence or imbalance of certain functional T cell subsets render SJL/J mice susceptible to EAE? 5) Can prothymocytes or the thymus from normal, genetically EAE-resistant mice render SJL/J mice resistant to EAE? We will use a quantitative adoptive transfer system between EAE-susceptible SJL/J (H-2s, Thy 1.2) and EAE-resistant B10.S (H-2s, Thy 1.1) mice to determine whether SJL/J prothymocytes can transfer the predisposition for the development of A-EAE and CR-EAE to naive B10.S recipients. Reciprocal prothymocyte transfer and thymus grafting experiments between SJL/J and B10.S mice will be used to test the possible role of intra- and extra-thymic environmental factors in determining EAE susceptibility or resistance. Prothymocyte mixing (competition) experiments will provide in vivo evidence for the role of modulator T cells in promoting or inhibiting EAE. The possible role of accessory cells in predisposing SJL/J mice to EAE will also be assessed in cell transfer experiments. In addition, we will trace the generation of EAE-specific functional T cell subsets (effector, suppressor, contrasuppressor) by SJL/J and B10.S prothymocytes. For this purpose, sensitized T cells of donor and host origin will be separated from the above chimeras according to their Thy 1 alloantigenic phenotypes, subfractionated according to their Lyt 2 phenotypes (Lyt 2+ or Lyt 2-), and tested for their ability to influence the blastogenic response to basic myelin protein in vitro and to induce or prevent the development of EAE in vivo.